Introduction: Breast cancer is the most common neoplasia of women from all over the world especially women from Colombia. 5%­10% of all cases are caused by hereditary factors, 25% of those cases have mutations in the BRCA1/BRCA2 genes. Objective: The purpose of this study was to identify the mutations associated with the risk of familial breast and/or ovarian cancer in a population of Colombian pacific. Methods: 58 high-risk breast and/or ovarian cancer families and 20 controls were screened for germline mutations in BRCA1 and BRCA2, by Single Strand Conformation Polymorphism (SSCP) and sequencing. Results: Four families (6.9%) were found to carry BRCA1 mutations and eight families (13.8%) had mutations in BRCA2. In BRCA1, we found three Variants of Uncertain Significance (VUS), of which we concluded, using in silico tools, that c.81­12C>G and c.3119G>A (p.Ser1040Asn) are probably deleterious, and c.3083G>A (p.Arg1028His) is probably neutral. In BRCA2, we found three variants of uncertain significance: two were previously described and one novel mutation. Using in silico analysis, we concluded that c.865A>G (p.Asn289Asp) and c.6427T>C (p.Ser2143Pro) are probably deleterious and c.125A>G (p.Tyr42Cys) is probably neutral. Only one of them has previously been reported in Colombia. We also identified 13 polymorphisms (4 in BRCA1 and 9 in BRCA2), two of them are associated with a moderate increase in breast cancer risk (BRCA2 c.1114A>C and c.8755­66T>C). Conclusion: According to our results, the Colombian pacific population presents diverse mutational spectrum for BRCA genes that differs from the findings in other regions in the country.

Hereditary breast cancer (BC) syndromes corresponds to 10% - 15% of all cases diagnosed worldwide. Most of these cases are due to deleterious germline genetic variants in BRCA1/2 genes; nevertheless, multipanel testing have contribute to the identification of other risk genes, including other homologous recombination (HR) repair genes, such as PALB2, ATM, CHEK2 and RAD51D. Here we explore the mutation spectrum of Hereditary Breast and Ovarian Cancer (HBOC) Colombian cases as part of the Hereditary Cancer Program from the National Cancer Institute from Colombia, the largest reference cancer center in the country, that seeks to identified high risk families to offer preventive measures and screening recommendations. A total of 358 patients fulfilling criteria for HBOC have been so far analyzed with Next Generation Sequencing using a multigene panel. Overall, 47% have negative results and in the 33% we identified VUSs. In general, 20% have a pathogenic or potentially pathogenic genetic variant; from those, BRCA1 (n = 17) and BRCA2 (n = 17) were the most frequently mutated genes (47.2% among all positive results). Deleterious mutations in RAD51D and PALB2 (also important HR repair genes) were found in 7% and 5.6% of the cases tested. Interestingly, genotype:phenotype correlations were found for these genes, as breast cancer molecular subtypes were distributed differently depending on the gene affected. In concordance with other reports, triple negative breast cancers (TNBC) were more frequent in BRCA1 (9/17, 53%) and PALB2 (4/4, 100%) carriers, and luminal subtypes were more frequent in BRCA2 carriers (10/17, 59%). Mutations in RAD51D: c.94_95del (p.Val32Phefs*67) and PALB2: c.2288_2291del (p.Leu763Ter), were both recurrent mutations in our Colombian cases. Further haplotype analysis will help us to determine if mutation carriers shared a common ancestry. Citation Format: Maria Carolina Sanabria-Salas, Ana Lucía Rivera-Herrera, Ana Milena Gómez-Camargo, Luis G. Carvajal-Carmona, Martha Lucía Serrano-López. Recurrent germline mutations in RAD51D and PALB2 are present in Colombian hereditary breast and ovarian cancer families [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1211.

Cancer is the second cause of mortality due to noncommunicable diseases in Colombia. In 2015 incident cases of breast (BC), gastric (GC), colorectal (CRC), and ovarian cancer (OC) attended at the Colombian National Cancer Institute (NCI) were 685, 498, 470, and 127, respectively. Although hereditary cancer syndromes are the minority of all cancer cases, the precise identification of individuals and relatives at high risk is a key aspect to the implementation of surveillance/screening, chemoprevention, and preventive surgery strategies for affected and unaffected carriers. In our country there are few studies conducted on hereditary cancer, and little is known about the spectrum of syndromes affecting Colombian families. In the Colombian NCI, we have designed and develop a comprehensive program for the registration, identification, diagnosis, management, and surveillance of cancer cases at high risk. Two main strategies where defined within this pilot program: 1) adjustment of the international protocols to the institutional context for identification and referral criteria of cancer patients with suspected syndrome to genetic counseling, genetic testing criteria, management, and surveillance, and 2) implementation of an institutional registry of patients with hereditary cancer, among other strategies. Also, first-degree relatives (FDR) of the affected carriers are offered to be tested and followed through the Center for Cancer Prevention and Early Detection (CPRED), recently established by the Colombian NCI. This Institutional ongoing program is providing genetic risk assessment to an average of 20 cancer patients per week since April 2018. The most frequent cancer we have attended is BC (56%), followed by CRC (10.5%), OC (6%), GC (5.5%), and others (22%). The average age at diagnosis was 47.3 for BC, 50.6 for CRC, 33.6 for OC, 39.4 for GC, and 47.8 years old (yo) for other cancers. Genetic testing has been offered to the patients according to the international guidelines. From all BC cases, the following fulfilled the Hereditary Breast and Ovarian Cancer (HBOC) criteria: i) 44.3% were diagnosed ≤ 45 yo, ii) 24% were diagnosed with triple-negative breast cancer (TNBC) at ≤ 60 yo, iii) 4% were TNBC cases diagnosed at > 60 yo + ≥ 1 FDR/second-degree relative with BC at < 50 yo, iv) 8% were patients with bilateral BC, v) 4% had a second primary tumor, and vi) 1.3% had Ashkenazi Jewish ancestry. From CRC cases, 50% were diagnosed at < 50 yo regardless of family history of gastrointestinal cancers and 30% were diagnosed at ≥ 50 yo and fulfilled criteria for Lynch or Li Fraumeni syndromes. In the case of GC, 60% of the patients had diffuse gastric cancer subtype at < 50 yo. Finally, all OC cases were submitted for genetic testing since all were diagnosed at < 50 yo; 43% were tested for HBOC since they corresponded to papillary serous subtype and 29% fulfilled criteria for Peutz Jeghers syndrome. To our knowledge, this is the first genetic cancer risk assessment program in the country, based in the largest Colombian cancer hospital. Citation Format: María Carolina Sanabria-Salas, Gonzalo Guevara-Pardo, Antonio Huertas, Vilma Medina, Ana Lucía Rivera-Herrera, Juan Carlos Mejía, Jesús Acosta, Carolina Wiesner-Ceballo. Program for the identification, management and monitoring of patients and families at high risk of cancer in a Colombian National Cancer Reference Institution [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A049.

Hereditary colorectal cancer (CRC) syndromes accounts for approximately 5-10% of total CRC cases. Among those, Lynch syndrome (LS) is the most frequent, but the penetrance depends on the mismatch repair gene (MMR) affected. On the other hand, the Familial Adenomatous Polyposis (FAP) syndrome is less frequent, but with penetrance near to 100%. In Colombia we don't know the prevalence of these syndromes. In the National Cancer Institute from Colombia, the largest reference cancer center in the country, we aim to performed germline genetic analyses in Colombian CRC patients with a suspected hereditary cancer syndrome, as part of the Hereditary Cancer Program that seeks to identified high risk families to offer preventive measures and screening recommendations. A total of 66 patients with CRC fulfilling criteria have been so far analyzed with Next Generation Sequencing using a multigene panel. From those, the 32% have negative results, 41% have VUSs and 27% have positive results (meaning a pathogenic or potentially pathogenic genetic variant). The most prevalent CRC syndrome is Lynch (11/18, 61% with MMR mutated genes), followed by polyposis syndromes such as FAP (11% APC) and MAP (1.5% biallelic MUTYH). Most of our Lynch syndrome families fulfilled Bethesda or Amsterdam criteria. Two recurrent mutations in MLH1 were found in Lynch syndrome families (6/11, 54.5%), which are MLH1: c.1918C>T (p.Pro640Ser) and MLH1: c.790+1G>A. Further haplotype analysis will help us to determine if mutation carriers shared a common ancestry. Citation Format: Ana Lucía Rivera-Herrera, Ana Milena Gómez-Camargo, Martha Lucía Serrano-López, Luis G. Carvajal-Carmona, María Carolina Sanabria-Salas. Novel and recurrent germline mutations in Colombian families with colorectal cancer syndromes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2356.